A comprehensive review of current therapeutic strategies in cancers targeting DNA damage response mechanisms in head and neck squamous cell cancer.

The DNA damage response (DDR) is an essential mechanism for maintaining genomic stability. Although DDR-targeted therapeutic strategies are being developed in several familial cancers, evaluation of their utility in head and neck squamous cell cancer (HNSCC) is lagging. This review briefly summarizes the mechanisms of DDR and the current knowledge on discovering DDR-related predictive biomarkers in HNSCC. This review also presents novel therapeutic strategies targeting DDR pathways for HNSCC based on the synthetic lethal concept. The combination of DDR inhibitors with cytotoxic treatments such as radiotherapy, chemotherapy, and immune checkpoint inhibitors is being evaluated, and several clinical trials are ongoing in patients with HNSCC. While DDR inhibitors are considered promising treatment options, resistance to these drugs is frequently observed, and their mechanisms are currently active research areas. A better understanding of the correlation between DDR pathways and cancer biology provides new therapeutic strategies for personalized medicine in HNSCC.